This proposal focuses on a newly recognized zinc metalloproteinase in the insulin-like growth factor (IGF) regulatory system, so-called pregnancy-associated plasma protein-A (PAPP-A), and its role in atherosclerosis. IGFs play a critical role in the vascular injury response through their potent and varied receptor-mediated effects on proliferation, migration, survival and differentiated cell function. PAPP-A is secreted by and binds to vascular cells, and, by proteolytic cleavage of local inhibitory IGF binding proteins, can increase the pericellular IGF available for receptor activation within the developing lesion. Strong PAPP-A immunoreactivity co-localizing with activated smooth muscle cells and macrophages has been demonstrated in vulnerable plaques of humans who had died of myocardial infarction with little or no staining in stable plaques. In addition, elevated serum PAPP-A is under consideration as a biomarker of acute coronary syndro muscle show accelerated atherosclerotic lesion development. Our overall hypothesis is that PAPP-A is a key regulatory factor promoting atherosclerotic plaque development and plaque vulnerability. Utilizing novel transgenic and conditional gene knock-out mice, the SPECIFIC AIMS of this proposal are to: 1. Ascertain the structural determinants of PAPP-A necessary for its ability to enhance atherosclerotic plaque development. 2. Determine the effect of PAPP-A deficiency on established atherosclerotic plaque. 3. Determine the effect of PAPP-A overexpression on plaque vulnerability. The proposed studies seek to gain a better understanding of PAPP-A in the fundamental biology of atherosclerosis, and should establish a scientific basis for novel strategies to identify and limit, and possibly reverse, plaque growth and vulnerability in atherosclerosis. PUBLIC HEALTH RELEVANCE: Atherosclerosis is the major cause of death in westernized societies. The proposed studies seek to gain a better understanding of a newly discovered enzyme implicated in atherosclerotic lesion development and should establish a scientific basis for novel strategies to identify and limit, and possibly reverse, atherosclerosis.